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GPR171, a Newly Deorphanized Hypothalamic G Protein‐Coupled Receptor is Involved in the Regulation of Reward‐Related Behaviors
Author(s) -
Bobeck Erin,
Gomes Ivone,
Fujita Wakako,
Devi Lakshmi
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1019.1
Subject(s) - hypothalamus , receptor , gene knockdown , neuropeptide y receptor , neuropeptide , medicine , endocrinology , antagonist , chemistry , microbiology and biotechnology , biology , biochemistry , gene
Recent neuropeptidomics studies have demonstrated that ProSAAS‐derived peptides, including BigLEN (b‐LEN) are abundant in the hypothalamus and enriched in the agouti related peptide (AgRP) neurons of the arcuate nucleus. Additional studies have implicated b‐LEN in acute feeding. Recently we deorphanized GPR171, as a G protein‐coupled receptor for b‐LEN. Overexpression of GPR171 leads to an increase and knockdown to a decrease in b‐LEN binding and signaling. In the hypothalamus GPR171 expression complements the expression of b‐LEN. Lentiviral shRNA‐mediated knockdown of GPR171 in the hypothalamus leads to alterations in food intake and metabolism. To further investigate the role of GPR171, we used a designer receptor exclusively activated by designer drugs (DREADD) approach to activate AgRP neurons leading to the release of b‐LEN (and other neuropeptides). As expected, activation of these neurons with clozapine‐N‐oxide leads to increases in food intake. Interestingly, this increase is attenuated by co‐administration of a GPR171‐selective small molecule antagonist. Given the known hedonic effects of activating these neuropeptide systems in the hypothalamus, we investigated additional reward‐related behaviors. We find that activation of AgRP neurons leads to a reduction in anxiety and depression. The specific role of b‐LEN/GPR171 in this phenomenon is currently being examined using GPR171 selective ligands. In addition, we find that stress alters GPR171 mRNA expresssion. In conclusion, GPR171 is the receptor for b‐LEN and plays a role in feeding and reward‐related behaviors. This work was supported in part by NIH grants NS026880 and DA019521 to L.A.D and a NIDA postdoctoral training grant DA007135 to E.N.B.